The human retroviruses HIV-1 and HTLV-1 can both infect the CNS causing the AIDS psychomotor complex and tropical spastic paraparesis, respectively. The goal of this project is to analyze the cell and molecular basis of the neurotropism of these human retroviruses. To this end, we have used primary cultures of adult human brain which can be enriched in microglia, astrocytes and oligodendrocytes. Our studies on HIV-1 infections in vitro indicate that the major target cell of the virus in the brain is the microglia, a cell of the monocyte-macrophage lineage. Neither astrocytes nor galactocerebroside-expressing oligodendrocytes can be productively infected in vitro. Moreover, no proviral DNA copies were found in these astrocytes derived from adult human brain. Similarly, a neuronal cell line induced to differentiate does not allow the virus to go through cycles of reverse transcription and replication. Thus, HIV- 1 entry and/or expression in neuroectoderm derivatives appears to be a rare event or inefficient process. We have shown before that only macrophage tropic strains replicate in microglia and that HIV-1 entry in microglia is mediated through the CD4 receptor. The region of the HIV-1 glycoprotein encompassing the V3 loop is critical for efficient entry in microglial cells as anti V3 antibodies can block infection of our brain cultures. Thus, therapeutic approaches to stop virus spreading to the brain could be targeted to the CD4 binding site or the specific V3 loop sequences of microglia tropic isolates. In our current experiments with HTLV-1, we are using similar approaches to determine in which cell of the nervous system this retrovirus can enter and replicate.